Gabapentinoids for Chronic Pain: Do the Harms Outweigh the Benefits?

Home , Gabapentinoid, Gabapentin enacarbil

iology es an th d s P e n a i n A Journal of Anesthesiology and Pain

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n Granger, J anesthesiol pain res 2018, 2:1

o h J Research

Review Article Open Access

Gabapentinoids for Chronic Pain: Do the Harms Outweigh the Benefits? Amy Kathryn Granger* Masters of Clinical Nursing, University of Tasmania, NSW Health, Royal North Shore Hospital, Australia *Corresponding author: Amy Kathryn Granger, Masters of Clinical Nursing, University of Tasmania, NSW Health, Royal North Shore Hospital, Australia, E-mail: [email protected] Received date: December 3, 2018; Accepted date: December 12, 2018; Published date: December 19, 2018 Copyright: © 2018 Granger AK. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

Abstract

Gabapentinoids, pregabalin (LyricaTM) and gabapentin (NeurontinTM) are anticonvulsants that have been approved for chronic pain conditions such as diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and are also widely prescribed off-label for chronic low back pain. Prescriptions for gabapentinoids have increased rapidly in the last five years, however, the evidence for its efficacy can be conflicting and will be analyzed for each of these chronic pain conditions. The adverse event rates and safety profile will be examined, including case reports of the occurrence of serious adverse events, to ascertain whether gabapentinoids have the potential to cause harm above the benefit of providing effective pain relief. Further case reports documenting serious withdrawal syndromes will add to the body of evidence to weigh the benefits over the risks and will identify areas where research is lacking. From the analysis of evidence on efficacy, adverse events and withdrawal there will be resulting recommendations for practice when considering gabapentinoid treatment for chronic pain.

Keywords: Lyrica; Gabapentin; Pregabalin; Anticonvulsants the literature around its efficacy for both on and off-label conditions. A Introduction look into the reporting of adverse events will provide an opportunity to examine the benefits against the potential harm. A final review of Chronic neuropathic pain, which is stated to persist over three evidence that demonstrates cases of withdrawal upon cessation of months, affects at least 10% of the population worldwide and is a major gabapentinoids will identify a major gap in research on this topic. burden to healthcare and the community [1]. A study conducted by Gaskin and Richard estimated the United States healthcare expenditure on chronic pain in addition to the added cost due to loss Background of productivity totals $635 billion dollars each year, exceeding the amount for heart disease, cancer and diabetes [2]. The International Prevalence Association for the Study of Pain defines neuropathic pain as a disease Within English-speaking nations, the increasing pattern of or injury to the central nervous system resulting in hyperexcitability of pregabalin prescriptions has been remarkably similar. In the United conducting somatosensory neurons within pain pathways [3]. This States, pregabalin prescriptions doubled between 2012 and 2016 [13], differs from nociceptive pain mechanisms that occur from thermal or also increasing by 150% in the United Kingdom from 2013 to 2018 mechanical tissue damage, such as that seen in acute pain from injury [14], and increasing by two and a half times in Australia from 2013 to or surgery [4]. 2016 [15]. There may be multiple influences for this trend, though In a multi-modal approach to treating chronic pain, gabapentinoid primarily the reluctance in primary care to prescribe opioids due to anticonvulsants, including pregabalin (LyricaTM, manufactured by concerns about addiction, dependence, and misuse is a contributing Pfizer Inc, New York, USA) and gabapentin (NeurontinTM, factor [16,17]; only fueled by the intensifying opioid crisis in the manufactured by Pfizer Inc, New York, USA) have become a favorable United States, with the Centre for Disease Control and Prevention option to treat neuropathic pain mechanisms, being recommended as reporting over 33,000 deaths involving an opioid in 2015, 5000 more first-line pharmacotherapy by the National Institute for Health and than the previous year [18]. Care Excellence [5], the Canadian Pain Society [6] and the When considering the increase in prescriptions, the incidence of the Neuropathic Pain Specialist Interest Group [7]. Gabapentin and chronic pain conditions for which gabapentinoids are approved should pregabalin are approved for use in postherpetic neuralgia, while be considered. The worldwide incidence of fibromyalgia is stated to be pregabalin is additionally approved to treat diabetic peripheral around 2.7% (range 0.5%-4%) [19,20], postherpetic neuralgia is said to neuropathy, fibromyalgia and central neuropathic pain [8]. Both are occur in 20%-30% of the population that develops the herpes zoster also currently widely prescribed off-label for chronic low back pain [9]. rash [21], also known as shingles; while 50% of all diabetics are said to Although pregabalin has been approved for use in chronic pain for suffer from diabetic peripheral neuropathy ten years post-diagnosis almost 15 years its popularity is rapidly increasing. Pregabalin is [22], making these conditions extremely widespread in current chronic currently ranked 8th in government drug spending in both the United pain management. In fact, pregabalin was the first drug to receive FDA States [10] and Australia [11]; while gabapentin prescriptions have approval for diabetic peripheral neuropathy and postherpetic neuralgia increased by 350% in the United Kingdom in the last five years [12]. [23] providing the only established medication option for this hard to With gabapentinoid therapy on the rise, it would be pertinent to review treat population.

J anesthesiol pain res, an open access journal Volume 2 • Issue 1 • 1000113 Citation: Granger AK (2018) Gabapentinoids for Chronic Pain: Do the Harms Outweigh the Benefits? J anesthesiol pain res 2: 113.

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In addition to the broadening of regulatory approval of pregabalin Efficacy for chronic pain conditions, up to 75% of prescriptions have been attributed to off-label conditions, primarily non-specific chronic low With prescriptions trends rapidly increasing, it is judicious to look back pain [9]. There is an age-related association with the incidence of into the evidence for the efficacy of gabapentinoids, most importantly chronic low back pain as demonstrated in the systematic review of 28 for the approved pain disorders of fibromyalgia, postherpetic studies by Meucci et al. that stated 4.2% of the population under forty neuralgia, and diabetic peripheral neuropathy. The Initiative on is affected, which increases to 19.6% up to those aged fifty-nine, and methods, measurement, and pain assessment in clinical trials group 25.4% of adults over the age of sixty [24]. The Global Burden of regarding a 50% pain reduction in participants from treatment as Disease Study ranked low back pain the highest cause of disability, clinically relevant, and ultimately, an effective pharmacotherapy; activity limitation and work absence than any other condition [25]. though 30% pain reductions are often also benchmarked for analysis [33]. Mechanism of action and pharmacokinetics Fibromyalgia is characterized by chronic widespread pain and stiffness in at least 11 of 18 specific tender points in the body which Neuropathic pain results from disease or injury to the usually accompany other symptoms such as fatigue and restless sleep somatosensory system causing neural excitability and increased [4], as well as mood disorders including anxiety and depression [31]. synaptic efficacy in central and peripheral pain pathways [26]. Both Originally, fibromyalgia was thought to be a rheumatologic condition pregabalin and gabapentin hold chemical similarity to Gamma- affecting the musculoskeletal system but it is now believed to be a Aminobutyric Acid (GABA) neurotransmitters, however, do not act on neurological condition which affects pain pathways [34]. This lead to any GABA receptors or synapses [27]. There are a couple of potential pregabalin becoming the first approved drug to treat fibromyalgia mechanisms which account for the analgesic effects of gabapentinoids; prompting a series of clinical trials often with conflicting findings. A these center around the reduction of pre-synaptic neurotransmitters meta-analysis by Straube et al. reported the results from five high- including glutamate, dopamine, norepinephrine, serotonin and quality randomized trials (n=3808) to conclude pregabalin is effective substance P which are responsible for initiating and sustaining and safe in treating this chronic condition [35]. However, when neuropathic pain states [28]. This is achieved as gabapentinoids bind to examining the data, only 21% (300mg daily dose) and 24% (600 mg the alpha-2-delta subunit of voltage-gated calcium channels which daily dose) of participants achieved 50% pain relief. Furthermore, 14% inhibit glutamate release [27]. Pregabalin has also been shown to target and 15% of participants attained the same level of pain relief with sodium-dependent ion channels significantly reducing the functional placebo, demonstrating the possibility that only a further 10% of response of glutamate; as well as modulating potassium channels participants received 50% pain relief due to the pregabalin. A similar inhibiting the release of substance P in the spinal cord [23]. These result was achieved with around 40% of participants having a 30% pain mechanisms provide pain relief by reducing the rapid nerve firing that reduction with pregabalin, where 28% achieved this outcome with occurs in neuropathic pain states. placebo, again achieving a result for a further 12% of participants. For While pregabalin and gabapentin have a similar mode of action and both outcomes, it could be argued that the result for pregabalin is chemical structure [29], pregabalin binds to receptors more efficiently, significant though not when compared to the high amount of placebo has greater bioavailability of up to 90%, and is more readily absorbed responders. Ultimately, the results showed only 10%-12% of making it four times more potent than gabapentin [30], thus requires participants gained pain relief above those who responded to placebo, significantly lower treatment doses. Additionally, properties including though it is impossible to determine exact efficacy rates caused pregabalin’s negligible protein binding and linear dosing kinetics limit exclusively by pregabalin. drug-drug interactions which have major advantages in combination The 2016 revised European League against Rheumatism guidelines therapy that chronic pain patients often require [31]. Gabapentin is does not support the prescribing of gabapentinoids for fibromyalgia prescribed less in primary care [11], possibly due to its short half-life despite the approval for use in neuropathic pain by the European and immediate release formulation making a less convenient three Medicines Agency [36]. This guideline was strongly influenced by a divided dose regime necessary, combined with decreased drug Cochrane review published by Uceyler et al. that reported the absorption and bioavailability as the dose increases. Pregabalin is supporting evidence as weak. Interestingly, this review has since been rapidly absorbed in the gastrointestinal tract, reaching peak plasma withdrawn due to competing and financial interests of the lead author within 60 to 90 minutes after administration in fasted subjects [4]. The [37]. However, the 2017 current Cochrane systematic review by Derry half-life is six hours and a steady state is achieved within two days of et al. analyzed eight studies with 3283 participants and reported that regular dosing; with both being primarily excreted through the only 1 in 10 people with moderate to severe neuropathic pain had a kidneys, with renal impaired patient’s requiring a 50% dose reduction significant drop in pain by 30%-50%; although, 80%-90% experienced [32]. In a multi-modal approach to treating chronic pain, adverse effects such as dizziness, drowsiness, weight gain and gabapentinoids are regarded as safe and have gained popularity in peripheral edema [38]. While the evidence to support the current pharmaceutical combination therapy to target neuropathic pain. European guidelines is withdrawn the available evidence continues to substantiate the recommendations against gabapentinoids for Evaluation fibromyalgia. To evaluate the harms against the benefits of utilizing Postherpetic neuralgia is a common neuropathic pain condition gabapentinoids for chronic pain there will be analysis into three caused by the re-activation of the varicella virus which causes the themes. Efficacy will examine the benefits, while adverse events and herpes zoster rash known as shingles. The herpes roster infection withdrawal will define potential harms. Through analysis of these affects the peripheral and central nervous system, causing themes, recommendations for practice and further research will be inflammatory neuron damage leading to the occurrence of identified. postherpetic neuralgia in about half of these patients [39]. This manifests as pain described as burning, throbbing, paraesthesia and

Page 3 of 9 itching in the affected region which can persist for several years A Cochrane systematic review by Moore et al., [57] compared the following the rash [39]. The research is divided on the efficacy of efficacy of pregabalin with postherpetic neuralgia, diabetic peripheral gabapentinoids for postherpetic neuralgia. One systematic review by neuropathy, and fibromyalgia. These results, displayed in the figure Edelsberg et al. benchmarked results based on an atypically low 25% (Figure 1), demonstrate the percentage of participants that reported reduction in pain, which found that 21% responded to gabapentin and 50% reductions in pain with daily doses of 150 mg, 300 mg and 600 mg 22.4% responded to pregabalin, being outperformed by other against placebo. The analysis showed that there is little benefit of 150 pharmacologic therapies that included antidepressants and opioids mg against placebo in all three pain conditions, with placebo [40]. This directly contrasts to a systematic review by Snedecor et al. outperforming 150 mg in fibromyalgia. Furthermore, the evidence that pooled data from seven studies to state pregabalin at or above showed only a small quantity of people will benefit from pregabalin for 300mg daily was the most effective pharmacotherapy to provide 30% fibromyalgia at any dose, which is consistent with the aforementioned and 50% reductions in pain scores [relative risk vs. placebo=2.44 and Cochrane review findings [38]. The 600 mg daily dose of pregabalin 2.13, respectively] [41]. A meta-analysis Zhang et al. included eleven provides 50% pain relief to an additional 30% of patients with trials to conclude gabapentin significantly reduced pain intensity postherpetic neuralgia and 22% of patients with diabetic peripheral compared to placebo [MD=−0.91, 95% CI −1.32 to −0.51, P<0.00001] neuropathy above placebo. However, both Moore et al., [57] and Zhang [42]. While the evidence is conflicting, the efficacy rates of et al., [43] have demonstrated the number of patients that benefit from gabapentinoids for postherpetic neuralgia are above those for other 600 mg, above a daily dose of 300 mg, is atypically small, bringing the neuropathic pain conditions. dose of 600 mg/day into serious question. Diabetic Peripheral Neuropathy (DPN) occurs in around a quarter of all diabetic patients with the prevalence increased to 50% for diabetics who have suffered the disease for over 25 years [43]. DPN involves neuropathic pain accompanied by loss of proprioception or temperature perception, caused by loss of nerve fibers, affecting the feet 96% of the time [43]. There are a plethora of studies that state pregabalin provides effective pain relief to these sufferers where inadequate treatment options were previously available [44-50]. Yet again, the effective pain relief of pregabalin that is reported typically occurs in only a small percentage of participants above placebo. Furthermore, the number of positive studies that have been sponsored by Pfizer, or conducted by consultants affiliated with Pfizer, brings a question of validity and bias over this body of evidence. It has been conferred that there is a major flaw in industry-funded research, which has been shown to produce more positive results over government- sponsored studies [51,52], conceivably due to bias in the choice of hypotheses tested, alterations with study designs and selective publication [53]. Figure 1: Data was taken from Moore et al., [57] on the efficacy of pregabalin against postherpetic neuralgia, diabetic peripheral There are two reviews conducted by Parson et al., [54] and Zhang et neuropathy, and Fibromyalgia. al., [43] that add to the body of evidence that supports pregabalin for DPN, both state that between 300 mg and 600 mg daily dose produces a significant reduction in pain scores. Though once again, over three- quarters of all the studies included in these reviews were sponsored by Chronic Low Back Pain (CLBP) was found by Giladi et al., [9] to be Pfizer. The meta-analysis by Zhang et al., showed pregabalin had the most prevalent indication, accounting for up to 30%, of off-label significantly lower mean point pain scores than placebo [MD=−0.79, prescriptions of pregabalin. Recently there have been three high- 95% CI−1.11 to −0.48, P<0.00001] evidenced through the duel analysis quality systematic reviews by Chou et al., [58], Enke et al. [59], and model of both random-effect and fixed-effect. However, five of the Shanthanna et al., [60] that reported on the efficacy of gabapentinoids included studies contrasted their analysis conclusion that pregabalin for CLBP. All three papers included an array of different studies due to was effective over placebo at achieving 50% pain reduction [43]. Zhang the reviewer’s inclusion and exclusion criteria, however, all three et al., [43] criticized the unfavorable pregabalin research in the systematic reviews concluded that there was no evidence to support analysis, stating population bias and study design flaws; including gabapentinoids for CLBP. Recent randomized controlled trials Ruack et al., [55] participants recognizing through informed consent conducted on participants with CLBP strengthen this body of evidence that the chance of placebo was only two out of seven whereby with Atkinson et al., [61] reporting gabapentin having no effect on participants assume a high chance of receiving the treatment drug pain scores; and Maitheson et al., [62] found no reduction in pain potentially altering pain scores. Ruack et al., [55] recognized that their intensity with pregabalin. A commonly cited study by Baron et al., [63] data of placebo outperforming pregabalin for DPN was largely stated when comparing pregabalin to placebo there was no difference unsupported by further research and were ultimately unable to in time to loss of therapeutic effect, which was calculated by a one- determine whether the drug, or trial, failed. The following year, point increase in weekly mean pain scores. There is an ever-increasing however, a large independent RCT (n=398) conducted by Smith et al., body of evidence against gabapentinoids for CLBP with a growing [56] showed similar findings that pregabalin did not significantly alter number of prescriptions indicating a trend against the current best the percentage of pain responders from that of placebo. evidenced-based practice that needs to be addressed.

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Adverse Events treatment and improved with discontinuation. Although sexual The most consistently reported Adverse Events (AE) that occur dysfunction is less reported in studies when assessing AE’s, there seems from gabapentinoids are dizziness, somnolence, peripheral edema and to be a high rate of occurrence above that of the most commonly weight gain, followed by dry mouth, blurred vision and ataxia [64-68]. reported AE’s. There have been supporting studies that also report Generally, it is stated that these AE’s occur in the early stages of erectile dysfunction caused by pregabalin [81,82], however, further initiating medication with side effects that resolve without the need to research would strengthen the need for patient assessment on sexual cease treatment [66,67]. Small variations in adverse event incidence function during treatment with this medication. arise with a review of industry-funded RCT’s by Freynhagen et al., [67] that reported rates of dizziness at 24%, somnolence 22%, and weight Case reports of serious cardiac AE’s can be found with Erdogan et gain at 6%; with Semel et al., [69] review along with the European al., [83] reporting on a patient with no cardiac history on 300 mg of Medicines Agency both reporting dizziness occurred in 31% and pregabalin daily for neuropathic pain that presented with peripheral somnolence in 22% of participants [70]. There is a consensus in edema, with normal hemodynamic parameters and kidney function. reporting that the rate of AE’s is dose-related which increases with Central edema with dyspnea and chest pain then developed with a higher doses [57,67-69]. In a large meta-analysis (n=5,802) by Zaccara computerized tomography scan finding cardiomegaly and pleural et al., [71] there was no clear relationship between AE’s to age, and effusion. Pregabalin was identified as the culprit and ceased whereby found no differences in the incidence between neuropathic pain the condition completely regressed. Gabapentin was then commenced, conditions; however, there are some conflicting results of minor with a similar development of symptoms, and was subsequently differences in occurrence rates between neuropathic pain conditions ceased. A report by Adar et al., [84] presents an 80-year-old female that [57,67,68]. suffered recurrent syncope attacks and chest pain with long QT syndrome that was attributed to pregabalin, again the condition There are AE’s, that while not having a significant impact on completely resolved with cessation of treatment. There are reports of systemic health, can have a massive impact on psychosocial function gabapentinoids exacerbating the severity of established chronic heart and quality of life; the most significant being a decline in cognitive failure [85,86], though due to the common occurrence of peripheral function, mood disorders, and suicidal ideation. There has been edema, the potential for the first onset of acute heart failure should not empirical research that has demonstrated both pregabalin and be overlooked. gabapentin have caused a significant decline in cognitive function [61,72]; though this has not often been studied in the context of the There are also cases of hemodynamic instability including two case impact on patients quality of life. There has been a significant reports by Bozikas et al., [87] and Kino et al., [88] that describe association with gabapentinoids and memory disorders which were pregabalin induced neutropenia that quickly resolved when the identified as poorly described within the literature [73,74]. The medication was discontinued. This resulted in their recommendations evidence to explain this cognitive decline has been provided by Eroglu for periodic monitoring of white blood cell counts for patients on high et al., [75] that discovered gabapentinoids block the formation of new dose regimens. There is also a total of seven case reports [89-95] found brain synapses in the central nervous system with pathological changes detailing comparable accounts of pregabalin-induced liver damage in synaptic plasticity thought to be responsible for memory defects where other causes were excluded. Duration of treatment spanned [76]. from two days to four months with doses from as little as 50 mg a day to the max dose of 600 mg. All reports detail worsening liver function For chronic pain patients, the worsening mood can have a large tests, at times resulting in jaundice. Liver function was restored with impact on functional ability. Pfizer [8] recommends the monitoring of the cessation of medication in all cases. patients initiating treatment with gabapentinoids for the emergence or worsening of mood disorders including depression and suicidal ideation. Pfizer states from 199 placebo-controlled trials the risk of Withdrawal suicidal ideation was 0.43%, double that of placebo, with four suicides To assess further harms, reports of withdrawal will be discussed. documented with pregabalin and none with placebo. This small The Lyrica monograph provided by Pfizer recommends a one week incidence contrast to other accounts such as Hall et al., [77] that details taper from a regular high dose pregabalin. This was demonstrated by five cases of worsening depression and suicidal ideation out of the fifty an industry-funded study published by Kasper et al., [96] that reported patients they had on gabapentinoid treatment. All cases had a history low-level discontinuation symptoms after 12 and 24 weeks of of depression, though had been stable at the time of initiating treatment. Though it could be argued that this ought not to be pregabalin, with improvements seen in all cases after treatment ceased. considered long-term treatment compared to patients whose treatment However, Kustermann et al., [78] reported a patient with the first spans years, even decades. With the longest trial included in this presentation of depression, or any psychiatric disorder, which resulted extensive review spanning less than one year, there is a gap of evidence in a suicide attempt two months after initiating pregabalin. The that needs to be addressed for long-term treatment patients regarding patient’s mental state stabilized and depressive symptoms resolved with the cessation of gabapentinoids. discontinuation of treatment. In contrast, reports of gabapentinoids providing improvements in depression further complicate this There are case reports in the literature that demonstrate serious evidence [79]. adverse events from patients in hard to treat acute withdrawal. Gahr et al., [97] report on a 38-year-old female patient with borderline Another AE having an impact on quality of life is the occurrence of personality disorder on 600 mg/day for two months, after the decision sexual dysfunction. A large case series observational study (n=75) by was made to wean and cease pregabalin due to no obvious indication Hamed [80] investigated the effect pregabalin has on sexual function to for treatment. This was achieved by a reduction of 25 mg a day down conclude that 32% suffered from anorgasmia, 35% had significant loss to 350 mg/day. The patient quickly developed psychomotor agitation, of libido and 51% of men suffered from erectile dysfunction. These arterial hypertension, tachycardia and tremor whereby another two- findings were not dose-related, occurred within weeks of initiating week detoxification regime was needed with inpatient monitoring.

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Barrett, Kittler and Singarajah [98] reported on a 61-year-old-male on consistently occurred in all treatment groups over placebo, with up to 300 mg/day of pregabalin for eight months, who then presented to 69% of patients experiencing at least one side effect [103]. The highest emergency with sudden and severe withdrawal symptoms of extreme occurring adverse events were universally reported as dizziness, combative agitation, diaphoresis, tachycardia, hypertension, tremor solmonance, peripheral edema, weight gain, dry mouth, blurred vision, and incontinent diarrhea needing ICU admission. The patient had a and ataxia. However, since efficacy rates can be as low as 25% with paradoxical reaction to benzodiazepine and lorazepam, with higher adverse event rates coupled with the potential for serious haloperidol and hydromorphone having little effect on his agitation. adverse events, individual patient assessment should be performed to Pregabalin was unable to be administered orally due to the patient's assess the benefit of continuing treatment with titration to the lowest confusion and physical inability to keep a nasogastric tube sited. dose that provides efficacy. While there is an abundance of data on the Sublingual clonidine was ultimately the only treatment that provided adverse event profile for short-term treatment, the question of long- any reduction in withdrawal symptoms. term consequences of taking anticonvulsants in the absence of seizures, including but not limited to cognitive function and withdrawal, should Hellwig et al., [99] also published a case report of a 53-year-old be the focus for continued research. woman, who ceased gabapentin due to the inability to ingest medications orally post endoscopy and band ligation. On day three, The Australian Pharmaceutical Benefits Scheme [104] reported 43% symptoms of agitation, anxiety, and confusion started with no response of patients had only one script of pregabalin filled, which has been to benzodiazepines. The symptoms worsened over the next days with supported by a large United States database observational study [105] disorientation, headaches and light sensitivity; whereby on day 5 that claimed the percentage of prescription refills was 52.6% and 56.9% gabapentin was reinitiated; the patients showed significant of patients that initiated therapy with gabapentin and pregabalin, improvement that evening and was calm, alert and orientated the next respectively. With such a large percentage of patient’s that discontinued morning. Mah and Hart [100] report on a 75-year-old woman who therapy with gabapentinoids, it could be argued that either there was a after a ten-day taper from 1800 mg of gabapentin developed clear lack of efficacy or cessation occurred due to adverse events. hypertension, chills, insomnia, nausea and severe abdominal cramps Wettermark et al., [106] conducted a database observational study in that were also unalleviated by benzodiazepines with blood tests and Sweden and only 21.5% of the patient’s taking pregabalin for scans providing no cause; however, symptoms completely resolved neuropathic pain continued to fill prescriptions after one year bearing three days after recommencing therapy at a renal adjusted dose. a striking resemblance to many efficacy rates reported in this review [35,38,40,41]. However, this is contrasted to the trend in the United A serious account by Barrueto et al., [101] saw a 34-year-old male States, Australia and the United Kingdom that see consistently rising present with status epilepticus, again unresponsive to lorazepam and prescription rates. diazepam, needing intubation plus IV phenobarbitone and phenytoin to stop the ninety-minute seizure. This was thought to be attributed to An interesting trend with studies within this review that measured a rebound release of glutamate involving the NMDA receptors. It is the efficacy of gabapentinoids for chronic pain conditions was the reported by Pfizer that sudden discontinuation of gabapentinoids can consistently high response rate to placebo [35,55-57]; whereby data cause seizures in epileptics, though this particular patient had no showed significant responders to treatment, however, not above those reports of previous seizures. This has been further documented in a which had a positive response to placebo. This was demonstrated with case report by Du et al., [102] when a middle-aged woman with Straube et al., [35] that showed a mere 10% of responders over that of diabetic peripheral neuropathy developed acute on chronic renal placebo. The placebo effect in pain management has long been impairment whereby pregabalin was ceased and not recommended. recognized and discussed. Neuro-anatomy of placebo analgesia is said Four days later the patient suffered her first tonic-clonic seizure with to involve an increase in activity in descending pain modulatory no further seizures after resuming treatment on a renal adjusted dose pathways as well as decreased activity in nociceptive pain processing of 75 mg/day. The possible initiation of seizures when ceasing pathways in the dorsal horn of the spinal cord [107]. Possible disease in gabapentinoids is a serious harm that should be taken into the peripheral nervous system, such as that in postherpetic neuralgia, consideration when planning cessation of treatment. could account for lower placebo response rates for these trials over fibromyalgia and diabetic peripheral neuropathy. There are also Discussion contextual influences that can trigger the placebo response including doctor-patient relationships, expectations, personal characteristics and The efficacy of gabapentinoids varies across different neuropathic even the therapeutic ritual itself which can be challenging to measure pain conditions. There is stronger evidence to support its use in and control [108]. diabetic peripheral neuropathy and postherpetic neuralgia over fibromyalgia, with no evidence for off-label use in chronic low back Placebo response rates in pain trials were found by Arakawa et al., pain. Although many reported studies find significant results with [109] to be increased by longer trial durations and flexible dose gabapentinoids there is not a single study included here that have regimens and decreased by increasing age and higher baseline pain achieved the primary outcome for more than 50% of participants, with intensity; ultimately recommending careful consideration to trial some as low as 21% [35,40]. This needs to be considered for planning and design. A review conducted by Castelnuovo et al., [108] practitioners initiating gabapentinoids, where evidence suggests that it determined that ‘the placebo effect’ had a moderate impact with is more likely to provide no effectiveness in reducing pain. Careful diabetic peripheral neuropathy, postherpetic neuralgia, and monitoring of reported pain scores should be performed with fibromyalgia trials, especially when compared to other pain conditions cessation of treatment for patients who receive little benefit. including complex regional pain syndrome and central neuropathic pain. With the placebo effect so prominent in pain trials it can prove With the lack of strong evidence for the efficacy of pregabalin, difficult to adequately assess the efficacy of the comparative drug especially for CLBP and fibromyalgia, the question of safety should bringing the results into question. Transparency with patients come to the forefront to assess benefit over risk. Adverse events regarding efficacy rates of gabapentinoids for their specific condition

Page 6 of 9 may aid in facilitating lower placebo responses to determine patients performed; with further research in this area desperately needed to who receive true benefit from treatment. This may provide more inform practitioners on appropriate supportive treatment options for accurate efficacy rates to aid in establishing a possible benefit for this population. All these aspects need to be considered on an patients. individual basis when assessing the benefit over the risks for the patient’s on gabapentinoids. The growing issue of industry-funded research influencing evidenced-based medicine for the benefit of pharmaceutical companies has been reported in many facets of healthcare. A Cochrane review by Conflicts of Interest Lundh et al., [110] concluded that industry-funded studies provided The author reports no conflicts of interest in this work. more favorable results and conclusions than independent research, which correlates to the trend in results discussed in this review. From all the studies included in this review, there are more industry-funded References studies than independent. This can be challenging when examining 1. Raffaeli W, Arnaudo E (2017) Pain as a disease: An overview. J Pain Res evidence as the poor methodology is not likely to account for the bias 10: 2003-2008. that occurs [111]. Though, industry-sponsored research should still be 2. Gaskin DJ, Richard P (2012) The economic costs of pain in the united highly scrutinized for the occurrence of bias including a close states. J Pain 13: 715-724. examination of methods used, data analysis and study design flaws, 3. What is neuropathic pain? (2015) International association for the study with pharmaceutical sponsorship itself to be considered a risk of bias of pain. [110]. 4. Sinatra RS, Jahr JS, Watkins-Pitchford JM (2010) The essence of analgesia and analgesics. Cambridge University Press, Cambridge, UK. Case reports of serious withdrawal from gabapentinoids [97-101] 5. Neuropathic pain in adults: Pharmacologic management in non-specialist raise issues with the recommended one week taper. Serious events settings (2013) National institute for health and care excellence (NICE). including acute withdrawal syndromes, intensive care admissions and 6. Moulin D, Boulanger A, Clark AJ, Clarke H, Dao T, et al. (2014) the onset of new seizures have been published. However, there is a Pharmacological management of chronic neuropathic pain: Revised major gap in the literature with no published trials that assess the consensus statement from the Canadian pain society. Pain res manag 12: potential impact that long-term treatment can have when patients face 15-21. the task of discontinuing these medications, with no clear indication in 7. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, et al. (2015) healthcare for appropriate withdrawal treatment [98]. A large portion Pharmacotherapy for neuropathic pain in adults: A systematic review and of gabapentinoid trials utilize a one-week titration to reach stable meta-analysis. Lancet Neurol 14: 162-173. treatment doses with a one week taper to discontinue; however, these 8. Tga ebusiness services. Product and consumer information (2016) Lyrica (pregablin). trails last twenty-four weeks at most, which could be argued as inadequate to correlate this to patients who have been on therapy for 9. Giladi H, Choiniere M, Fitzcharles MA, Ware MA, Tan X, et al. (2015) Pregabalin for chronic pain: Does one medication fit all? Curr Med Res many years. Unfortunately, a quantitative trial design to research this Opin 31: 1403-1411. issue would prove difficult, including recruiting a very specific 10. Aitken M, Kleinrock M (2017) Medicines use and spending in the US. population that has been on long-term gabapentinoids that are willing Australian government department of health pharmaceutical benefits to cease their medication; though, qualitative trials may shed light on 11. scheme. the experiences endured by this specific population. Practitioners 12. Iacobucci G (2017) UK government to reclassify pregabalin and should recognize that serious complications can arise from gabapentin after rise in deaths. BMJ 358: j4441. gabapentinoid withdrawal and an extended taper with patient 13. Johansen ME (2018) Gabapentinoid use in the United States 2002 monitoring in primary care should be considered for long-term treated through 2015. JAMA Intern Med 178: 292-294. patients. 14. Croker R, Smyth D, Walker AJ, Goldacre B (2018) The clinician impact and financial cost to the nhs of litigation over pregabalin: A cohort study Conclusion in english primary care. BMJ Open 8: e022416. 15. Cairns R, Schaffer AL, Ryan N, Pearson SA, Buckley NA (2018) Rising With the use of gabapentinoids rapidly increasing in pain pregabalin use and misuse in Australia: Trends in utilization and management and the large amount of conflicting evidence to support intentional poisonings. Addiction. this trend, it can become difficult for clinicians to align with the 16. Blake H, Leighton P, van der Walt G, Ravenscroft A (2015) Prescribing current best evidenced-based practice. Gabapentinoids should not be opioid analgesics for chronic non-malignant pain in general practice- A prescribed for chronic low back pain and caution should be used in survey of attitudes and practice. Br J Pain 9: 225-232. fibromyalgia, for which there is conflicting evidence. Initiating 17. Mafi JN, McCarthy EP, Davis RB, Landon BE (2013) Worsening trends in gabapentinoids for patient’s suffering from postherpetic neuralgia and the management and treatment of back pain. JAMA Intern Med 173: diabetic peripheral neuropathy should be closely supervised, with a 1573-1581. focus on the level of pain reduction achieved. There should be swift 18. Rudd RA, Aleshire N, Zibbell JE, Gladden RM (2016) Increases in drug and opioid overdose deaths-united states, 2000-2014. MMWR Morb discontinuation of therapy for patients where gabapentinoids prove Mortal Wkly Rep 64: 1378-1382. not effective. With little evidence to support the efficacy of a 600 mg 19. Queiroz LP (2013) Worldwide epidemiology of fibromyalgia. Curr Pain daily dose of pregabalin, coupled with the high potential for adverse Headache Rep 17: 356. events, practitioners should consider a maximum dose of 300 mg. 20. Bhusal S, Diomampo S, Magrey MN (2016) Clinical utility, safety, and Close monitoring of less reported side effects throughout long-term efficacy of pregabalin in the treatment of fibromyalgia. Drug Healthc treatment should be performed, including, but not limited to, cognitive Patient Saf 8: 13-23. decline and mood disorder assessment, with cardiac, liver, kidney and 21. Mallick-Searle T, Snodgrass B, Brant JM (2016) Postherpetic neuralgia: sexual function also monitored. A slow monitored taper for patient’s Epidemiology, pathophysiology, and pain management pharmacology. J that wish to discontinue from long-term treatment should be Multidiscip Healthc 9: 447-454.

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